Pharmacovigilance. Interaction with the Regulatory Agency. Murilo Freitas Dias ! "#$ Salvador September 26, 2006

Transcription

1 Interaction with the Regulatory Agency Pharmacovigilance! "#$ Salvador September 26, 2006

2 Drug Safety Knowledge is gained either by experience, learning and perception or through association and reasoning Drug Safety Knowledge Time Pre-Marketing Evaluation Phase I Phase II Phase III Licencing Post-Marketing Evaluation Toxicity Unexpected effects in in some patients Cancer Idiosyncratics events Clinical Trials Pharmacovigilance

3 World safety facts about medicines More than 130 pharmaceutical products have been withdrawn from various markets over the past 40 years 1/3 within two years of launch; 50% within 5 years. The most frequent problems are: ADRs hepatic, hematological and cardiovascular complications Source: Management of Safety Information from Clinical Trials. Report of CIOMS Working Group VI p. 22

4 Voluntary withdrawn from the market for safety reasons (e.g) Cerivastatin and Rhabdomyolysis August 2001 Rofecoxib and Cardiovascular effects October 2004 Time

5 Why drug safety issues may not be indentified until the post-marketing periode? 1. The adverse reaction is rare and therefore undetectable until large number of patients have been exposed to the drug 2. There is a long latency between starting the drug and development of the adverse reaction 3. The drug has not been studies in normal clinical practice Source: Waller PC, Arlett P. Responding to signals. In: Pharmacovigilance. Mann R, Andrews E, editors. Wiley Chicester 2002

6 WHO Pharmacovigilance definition The Importance of Pharmacovigilance, WHO 2002

7 The aims of pharmacovigilance in relation to the use of medicines improve patient care and safety improve public health and safety detect problems related to the use of medicines and communicate the findings in a timely manner; contribute to the assessment of benefit, harm, effectiveness and risk Source: The safety of medicines in public health programmes: pharmacovigilance an essential tool. WHO, 2006 P. 9

8 The aims of pharmacovigilance in relation to the use of medicines (cont.) leading to the prevention of harm and maximization of benefit; encourage the safe, rational and more effective (including cost-effective) use of medicines; and promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public. Source: The safety of medicines in public health programmes: pharmacovigilance an essential tool. WHO, 2006 P. 9

9 Patient impact of Adverse events Drug-related problems [Adverse Drug Event and Medication Errors] (in time of hospitalization) 20 72% Drug permanent disabilities and deaths 7 12% Source: T Vira, M Colquhoun, E Etchells. Reconcilable differences: correcting medication errors at hospital admission and discharge. Qual Saf Health Care 2006;15:

10 How can we get drug safety information? Spontaneous Reports - Healthcare professionals - Other Literature The internet Solicited reports (How do you fill?) Clinical trial reports Epidemiology and Observational studies Disease registries and Regulatory databases Licensor-license interactions Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V

11 Standard Regulatory Requirement for Spontaneous Reports Serious suspected reactions (15 days) Non-serious suspected reactions (line-listing withing PSUR) SUSAR (7 calendar days) Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V

12 There are two principal criteria that control the priority for documenting, validating, evaluating and regulatoryreporting of ADR cases: Seriousness Expectedness Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V p. 109

13 Serious Adverse Event or Reaction: Seriousness Standard Criteria Any untoward medical occurrence that at any dose: Results in death Is life-threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity, or Is a congenital anomaly/birth defect Source: Management of Safety Information from Clinical Trials. Report of CIOMS Working Group VI p. 236

14 Unexpected ADR An adverse reaction, the nature or severity of which is not consistent with the applicable product information Listed or unlisted (in association with the Company Core Safety Information [CCSI]) Labeled or unlabeled (in connection with official product information for marketed medicines, such as package insert, SPC or data sheets Source: ICH Guideline: E6 Good Clinical Practice

15 Frequency of ADRs In evaluating clusters of cases as opposed to individual cases, the newly observed (estimated) frequency of occurrence may be unexpected relative to the information in Reference Safety Information (e.g., RSI may state an ADR is rarely but new signals say, at least uncommon ) Very common Common (frequent) Uncommon (infrequent) Rare Very rare 1/10 ( 10%) 1/100 and <1/10 ( 1% and < 10%) 1/1000 and <1/100 ( 0.1% and < 1%) 1/10,000 and <1/1000 ( 0.01% and < 0,1%) < 1/10,000 (<0.01%) Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V p. 122

16 Signal A report or reports of an event with an unknown causal relationship to treatment that is recognized as worthy of further exploration and continued surveillance. Source: Management of Safety Information from Clinical Trials. Report of CIOMS Working Group VI p. 237

17 The discovery of an adverse drug effect 100 % // Knowledge of the adverse effect (%) 0 % // Signal assessment Sinal generation Signal strengthening Signal follow-up time Fonte: Meyboom et al. Principles of segnal detection in pharmacovigilance. Drug Saf (6) (376)

18 Relation between case reports and epidemiology Statistical Evidence Pharmacovigilance (Hypotesis generation) Pharmacoepidemiology (Hypotesis testing) Clinical & pharmacological information Source: A. C. van Grootheest. Improving pharmacovigilance and the role of the pharmacist. P. 68 (modified)

19 Priority for handling and follow-up ADRs Serious unexpected and special interest cases Serious expected and non-serious unexpected cases Non-serious, expected cases Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V p

20 Different types of reports by Pharmaceutical companies US NDA - Quarterly - Annual ICH PSUR - 6-month - One-year Five-year relicensing Six-year relicensing (for Japan) Source: Current Challenges in Pharmacovigilance: Pragmatic Approaches. Report of CIOMS Working Group V p

21 Benefit-risk analysis The Benefit The Risk Drug s positive effect on disease reduction, prevention or elimination Negative effect expressed as unwanted or unanticipated adverse outcomes Source: Holden, William L. Benefit-Risk Analysis. A Brief Review and Proposed Quantitative Approaches. Drug Safety 2003, 26 (12),

22 Benefit/risk evaluation and regulatory action Indications - Limiting the indications for which the benefits are insufficient to jusfity use - For which use is associated with a greater risk of the ADR Dose - Reductions in dose - Limitation on duration of treatment (e.g. ADRs related to cumulative dose) Contraindications - Addition of concomitant diseases and/or medications Source: Davies s Textbook of Adverse drug reactions. Fifth ed. Chapman & Hall Medical. DM, Davies. p

23 Benefit/risk evaluation and regulatory action Drug interactions - Addition of concomitant medications which interact Pregnancy/lactation - Addition of new information Warnings - Addition of concomitant diseases and/or medication to be carefully weighed against the benefits Undesirable effects - Addition of newly recongnized adverse reactions Source: Davies s Textbook of Adverse drug reactions. Fifth ed. Chapman & Hall Medical. DM, Davies. p

24 Food and Drug Administration (e.g) Guidance for Industry. Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (2005) Other

25 ICH CLINICAL SAFETY DATA MANAGEMENT (e.g) DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING E2A (1994 Step 5) DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS E2B(M) ( Step 5) PERIODIC SAFETY UPDATE REPORTS FOR MARKETED DRUGS E2C(R1) (1996 Step 5 e Addendun )

26 ICH POST-APPROVAL SAFETY DATA MANAGEMENT (e.g) DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING E2D (2003 Step 5) PHARMACOVIGILANCE PLANNING E2E (2004 Step 5)

27 European Medicines Agency (e.g) THE EXPOSURE TO MEDICINAL PRODUCTS DURING PREGNANCY: NEED FOR POST- AUTHORISATION DATA (2006) 5en.pdf VOLUME 9 PHARMACOVIGILANCE. Medicinal Products for Human use and Veterinary Medicinal Products (2004) pdf

28 (e.g) MHRA Statutory Pharmacovigilance Inspection _PAGE&nodeId=826

29 Guidelines on the reporting of adverse drug reactions by drug sponsors (July 2005) Australian guideline for pharmacovigilance responsibilities of sponsors of registered medicines regulated by drug safety and evaluation branch

30 CIOMS -Council for International Organizations of Medical Sciences (Publications) CIOMS I - Expedited Reporting of Individual ADRs CIOMS 1A - Harmonisation of Data Elements and Fields for Electronic Reporting of Individual ADRs CIOMS II - Periodic Safety Updates CIOMS III - Core Clinical-Safety Information CIOMS IV - Benefit-Risk Evaluation

31 CIOMS -Council for International Organizations of Medical Sciences Management of Safety Information from Clinical Trials Report of CIOMS Working Group VI (2005) Current challenges in pharmacovigilance pragmatic approaches report of CIOMS Working Group V (2001) Pharmacogenetics Towards improving treatment with medicines (2005) SMQs Development and Rational Use of Standardised MedDRA Queries (2004) (Standardised MedDRA Queries)

32 CIOMS Working Groups on Drug Safety (in process) CIOMS WG VII on Development Safety Update Report (DSUR) CIOMS WG on Signal Detection: Points to consider CIOMS WG on Vaccine Pharmacovigilance DRUG DEVELOPMENT RESEARCH IN RESOURCE-LIMITED COUNTRIES. How to succeed in implementation of Good Clinical Practice Guidelines

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34 PANDRH OPERATING SYSTEM NAFTA SICA CARICOM Pan American Conference Secretariat Andean Area MERCOSUR Regulators Consumers Academia Professional Ass Industry Steering Committee WG WG WG WG WG WG

35 1. GMP (FDA, USA) 2. BE (FDA, USA) 3. GCP (ANMAT, Argentina) 4. D. Counterfeiting (ANVISA, Brazil) 5. D. Classification (MOH, Costa Rica) 6. Drug Approval (Registration) (MOH, Venezuela) 7. Pharmacopoeia (USP) 8. Medicinal Plants (MOH, Jamaica) 9. Pharmacovigilance (INVIMA, Colombia) 10. GLP (ISP, Chile) 11. Drug Promotion (ANVISA, Brazil) 12. Vaccines (MOH, Cuba)

36 PANDH WG/Phv: Mission To develop and strengthen pharmacovigilance through activities and proposals of harmonized regulatory actions that promote the safe and rational use of drugs as a necessary component of Public Health policies in the Region of the Americas

37 PANDH WG/Phv: Objectives 1. To promote the development and dissemination of knowledge, criteria and methodologies in pharmacovigilance to be used in training activities 2. To review and develop tools to support harmonization in pharmacovigilance 3. To design a system that support the work in network to improve and strengthen exchange communication knowledge and decision making in the area of pharmacovigilance. 4. To foster integration of pharmacovigilance as part of drug policy and public health programs 5. To promote and disseminate research on pharmacovigilance and evaluation of their impact in public health and patient safety

38 Brazilian Drug Marketing 551 Pharmaceutical Companies 56,138 Community Pharmacies 40,000 Pharmaceutical Products 10,000 Drugs 8,000 Hospitals More than 180,000,000 inhabitants

39 Brazilian Drug Monitoring Centre (CNMM) Pharmacovigilance Unit/NUVIG Pharmacovigilance Unit (CNMM) Programms Working Groups Risk Evaluation Team N#1 (ATC: C, D, G, H, M, N e R ) Sentinel Hospitals Risk Evaluation Team N#2 (ATC: A, J, B, L, S, V e P ) Risk and Crises Management Reporting Pharmacies Regional Pharmacovigilance Centres Pharmaceutical Companies Safety and Rational Drug Use promotion Database Team Alerts and Information Pharmacists: 12 Physicians: 3 Administrative: 2

40 9 Regional Pharmacovigilance Centres Brasil Mato Grosso (2006) Ceará (2001) Goiás (2004) Bahia (2005) São Paulo (2001) Paraná (2005) Mato Grosso do Sul (2006) Rio de Janeiro (2005) Santa Catarina (2004)

41 Health Professionals ADR Form Eletronic Internet on-line form Internet PDF

42 Brazilian Medication Error Report Form Internet PDF

43 Assessment of Adverse events: causality (Algorithm or Global Instropection) - + not related unlikely possibly probably definitely 0 % 100 % Probability

44 176 Sentinel Hospitals North - 17 hospitals Northeast - 39 hospitals Middle East - 12 hospitals Southeast - 77 hospitals South - 31 hospitals Hospital Pharmacovigilance Programme (Since 2001) Sentinels: 104 ; Collaborators: 72

45 Community Pharmacies Pharmacovigilance Programme (Since 2005) If you have problems with medicines? Look for the Pharmacist 1655 Reporting Pharmacies and 4120 Pharmacists in (500 reports)

46 Accumulative Reports per Year received by Brazilian Centre for Drug Monitoring (CNMM) Reports *

47 The knowledge-driven model of Data decision-making Information Collection Knowledge Sorting/ selection Understanding Analysis Judgement Interpretation Decision Weghing options Report Valuation Source: Design and Implementation of Health Information Systems. WHO, p. 35 (modified)

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